Osteopetrorickets: two contradictory patterns-one unifying diagnosis.

A 5-month-old infant with bone findings on x-ray presented an apparent contradiction including findings of both diffusely dense bones and rickets in the context of a history and laboratory investigation that suggested leukemia. Next generation gene panel sequencing revealed a TCIRG1 mutation which is consistent with autosomal recessive osteopetrosis. The paradoxical x-ray findings underscore a recently elucidated mechanism for the pathogenesis of a TCIRG mutation. This case highlights the importance of recognizing this radiographic, seeming contradictory, association in the context of a confusing clinical presentation. Failure to recognize this pattern promptly may lead to a delay in diagnosis, thus potentially permanent organ failure.

Radiologists' Diagnostic Performance in Differentiation of Rickets and Classic Metaphyseal Lesions on Radiographs: A Multicenter Study.

BACKGROUND. Despite evidence supporting the specificity of classic metaphyseal lesions (CML) for the diagnosis of child abuse, some medicolegal practitioners claim that CML result from rickets rather than trauma. OBJECTIVE. The purpose of this study was to evaluate radiologists' diagnostic performance in differentiating rickets and CML on radiographs. METHODS. This retrospective seven-center study included children younger than 2 years who underwent knee radiography from January 2007 to December 2018 and who had either rickets (25-hydroxyvitamin D level < 20 ng/mL and abnormal knee radiographs) or knee CML and a diagnosis of child abuse from a child abuse pediatrician. Additional injuries were identified through medical record review. Radiographs were cropped and zoomed to present similar depictions of the knee. Eight radiologists independently interpreted radiographs for diagnoses of rickets or CML, rated confidence levels, and recorded associated radiographic signs. RESULTS. Seventy children (27 girls, 43 boys) had rickets; 77 children (37 girls, 40 boys) had CML. Children with CML were younger than those with rickets (mean, 3.7 vs 14.2 months, p < .001; 89.6% vs 5.7% younger than 6 months; 3.9% vs 65.7% older than 1 year). All children with CML had injuries in addition to the knee CML identified at physical examination or other imaging examinations. Radiologists had almost perfect agreement for moderate- or high-confidence interpretations of rickets (κ = 0.92) and CML (κ = 0.89). Across radiologists, estimated sensitivity, specificity, and accuracy for CML for moderate- or high-confidence interpretations were 95.1%, 97.0%, and 96.0%. Accuracy was not significantly different between pediatric and nonpediatric radiologists (p = .20) or between less experienced and more experienced radiologists (p = .57). Loss of metaphyseal zone of provisional calcification, cupping, fraying, and physeal widening were more common in rickets than CML, being detected in less than 4% of children with CML. Corner fracture, bucket-handle fracture, subphyseal lucency, deformed corner, metaphyseal irregularity, and subperiosteal new bone formation were more common in CML than rickets, being detected in less than 4% of children with rickets. CONCLUSION. Radiologists had high interobserver agreement and high diagnostic performance for differentiating rickets and CML. Recognition that CML mostly occur in children younger than 6 months and are unusual in children older than 1 year may assist interpretation. CLINICAL IMPACT. Rickets and CML have distinct radiographic signs, and radiologists can reliably differentiate these two entities.

Artificial intelligence research within reach: an object detection model to identify rickets on pediatric wrist radiographs.

BACKGROUND: Artificial intelligence models have been successful in analyzing ordinary photographic images. One type of artificial intelligence model is object detection, where a labeled bounding box is drawn around an area of interest. Object detection can be applied to medical imaging tasks. OBJECTIVE: To demonstrate object detection in identifying rickets and normal wrists on pediatric wrist radiographs using a small dataset, simple software and modest computer hardware. MATERIALS AND METHODS: The institutional review board at Children's Healthcare of Atlanta approved this study. The radiology information system was searched for radiographic examinations of the wrist for the evaluation of rickets from 2007 to 2018 in children younger than 7 years of age. Inclusion criteria were an exam type of "Rickets Survey" or "Joint Survey 1 View" with reports containing the words "rickets" or "rachitic." Exclusion criteria were reports containing the words "renal," "kidney" or "transplant." Two pediatric radiologists reviewed the images and categorized them as either rickets or normal. Images were annotated by drawing a labeled bounding box around the distal radial and ulnar metaphases. The training dataset was created from images acquired from Jan. 1, 2007, to Dec. 31, 2017. This included 104 wrists with rickets and 264 normal wrists. This training dataset was used to create the object detection model. The testing dataset consisted of images acquired during the 2018 calendar year. This included 20 wrists with rickets and 37 normal wrists. Model sensitivity, specificity and accuracy were measured. RESULTS: Of the 20 wrists with rickets in the testing set, 16 were correctly identified as rickets, 2 were incorrectly identified as normal and 2 had no prediction. Of the 37 normal wrists, 33 were correctly identified as normal, 2 were incorrectly identified as rickets and 2 had no prediction. This yielded a sensitivity and specificity of 80% and 95% for wrists with rickets and 89% and 90% for normal wrists. Overall model accuracy was 86%. CONCLUSION: Object detection can identify rickets on pediatric wrist radiographs. Object detection models can be developed with a small dataset, simple software tools and modest computing power.

Vitamin D, rickets and child abuse: controversies and evidence.

Suboptimal vitamin D status is a global health issue that affects children and adults worldwide. The prevalence of vitamin D deficiency and insufficiency has been well documented in the pediatric population in the United States. Although vitamin D deficiency is common, radiographic findings are uncommon and can be subtle. Additionally, because of the high prevalence of pediatric vitamin D insufficiency, it is commonly identified in young children with fractures. However, the majority of pediatric fractures are caused by trauma to healthy bones. Some, especially in infants and toddlers, are caused by non-accidental trauma. A small percentage is related to medical disease, including those associated with disorders of collagen, disorders of mineralization, and non-fracture mimics. Despite the scientific evidence, among disorders of mineralization, non-rachitic disorders of vitamin D have become a popular non-scientific theory to explain the fractures identified in abused children. Although infants and young children with rickets can fracture bones, the vast majority of fractures identified in abused infants are not caused by bone disease. Here we present a review of the literature on bone disease in the setting of accidental and non-accidental trauma. This context can help physicians remain vigilant about identifying vulnerable young children whose injuries are caused by non-accidental trauma.

Rachitic change and vitamin D status in young children with fractures.

OBJECTIVE: To examine the association between rachitic changes and vitamin D levels in children less than 2 years old with fractures. METHODS: Children less than 2 years old who were admitted to a large children's hospital for a fracture and underwent a skeletal survey were included. Two pediatric radiologists blinded to the children's vitamin D levels independently reviewed the skeletal surveys for the following rachitic findings: demineralization, widened sutures, rachitic rosary, Looser zones, and metaphyseal changes. Kappa coefficients were calculated to assess inter-rater agreement. Logistic regression was used to test the association between vitamin D level and rachitic findings. RESULTS: There were 79 subjects (40 female and 39 male) with a median age of 4 months. Vitamin D levels ranged from 11.6 to 88.9 ng/ml and were low in 27. Questionable demineralization was noted in seven subjects; mild to moderate demineralization was observed in four subjects. Widened sutures were noted in seven subjects, many also with concurrent intracranial hemorrhage. Lower vitamin D levels were associated with increased odds of demineralization after adjusting for age, gender, and prematurity (P < 0.015). An association was not found between the vitamin D level and suture widening (P = 0.07). None of the cases demonstrated Looser zones, rachitic rosary, or metaphyseal changes of rickets. CONCLUSIONS: Infants and toddlers with fractures frequently have suboptimal vitamin D levels, but radiographic evidence of rickets is uncommon in these children.

Micro-CT assessment of dental mineralization defects indicative of vitamin D deficiency in two 17th-19th century Dutch communities.

OBJECTIVES: This study investigates vitamin D deficiency patterns in individuals from birth to the beginning of adolescence. Microscopic computed tomography (micro-CT) evaluation of interglobular dentine (IGD) in teeth provides information on the age of disease onset and the number of deficient periods per individual, which will increase our understanding of factors influencing vitamin D deficiency prevalence, including sociocultural practices and latitude. MATERIALS AND METHODS: Beemster and Hattem, two Dutch 17th-19th century communities, yielded relatively high prevalences of rickets (15-24%) and residual rickets (15-24%). From the affected individuals, a subsample of 20 teeth were selected for micro-CT scanning. Thin sections were made of 17 teeth, consisting of 6 teeth with and 11 teeth without observable IGD on micro-CT that were included for method comparison. RESULTS: About 19 out of 29 (65.5%) individuals (one tooth was deemed unobservable) presented with IGD on micro-CT. Eight of the 11 (72.7%) individuals without IGD on micro-CT demonstrated histologically visible IGD. In 40.7% (11/27) of the affected individuals (combined micro-CT and histology results), vitamin D deficiency was recurrent, and in four individuals, some episodes occurred at approximately annual intervals suggesting vitamin D deficiency was seasonal. In three individuals, IGD occurred in the dentine formed around birth, suggesting maternal vitamin D deficiency. DISCUSSION: Micro-CT analysis of IGD is found to be a valuable non-destructive method that can improve our understanding of the influence of sociocultural practices and latitude on disease development within age and sex groups in past communities.

Selective rickets from localized advanced maturation-a case report.

An unusual cause of rickets is illustrated by a patient with infantile multisystem inflammatory disease who, by age 2 years and 4 months, developed striking radiographic and clinical rickets restricted to those joints involved by the inflammatory process. The locally increased vascularity from his inflammation led to increased maturation at those sites so rapid as to override the usual enchondral calcification, thus causing a rickets pattern. Other sites, such as the proximal humeri, lacking any inflammation, showed no increased maturation rate and did not manifest local rickets. Rapid local bone maturation may cause localized rickets.

The Primary Physis.

The primary physis is responsible for long bone growth in children and adolescents. Injury and physiologic or metabolic stress to the primary physis present unique radiologic findings that are important for radiologists to recognize and diagnose. Appreciation of the anatomy and histology of the primary physis forms the basis for understanding the imaging findings associated with pathologic conditions affecting the primary physis. Salter-Harris injuries, physeal bars, growth arrest lines, rickets, and focal periphyseal edema zones are common conditions with recognizable radiologic presentations. Proper diagnosis of these primary physeal conditions will aid in the treatment of affected pediatric patients.

Enzyme-replacement therapy in life-threatening hypophosphatasia.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

Comparison of Limestone and Ground Fish for Treatment of Nutritional Rickets in Children in Nigeria.

OBJECTIVE: To determine whether children with calcium-deficiency rickets respond better to treatment with calcium as limestone or as ground fish. STUDY DESIGN: Nigerian children with active rickets (n = 96) were randomized to receive calcium as powdered limestone (920 mg of elemental calcium) or ground fish (952 mg of elemental calcium) daily for 24 weeks. Radiographic healing was defined as achieving a score of 1.5 or less on a 10-point scale. RESULTS: The median (range) age of enrolled children was 35 (6-151) months. Of the 88 children who completed the study, 29 (66%) in the ground fish group and 24 (55%) in the limestone group achieved the primary outcome of a radiographic score of 1.5 or less within 6 months (P = .39). The mean radiographic score improved from 6.2 ± 2.4 to 1.8 ± 2.2 in the ground fish group and from 6.3 ± 2.2 to 2.1 ± 2.4 in the limestone group (P = .68 for group comparison). In an intention to treat analysis adjusted for baseline radiographic score, age, milk calcium intake, and serum 25-hydroxyvitamin D concentration, the response to treatment did not differ between the 2 groups (P = .39). Younger age was associated with more complete radiographic healing in the adjusted model (aOR 0.74 [95% CI 0.57-0.92]). After 24 weeks of treatment, serum alkaline phosphatase had decreased, calcium and 25-hydroxyvitamin D increased, and bone mineral density increased in both groups, without significant differences between treatment groups. CONCLUSION: In children with calcium-deficiency rickets, treatment with calcium as either ground fish or limestone for 6 months healed rickets in the majority of children.

Bone Disease in the Common Marmoset: Radiographic and Histological Findings.

The common marmoset (Callithrix jacchus) is a New World primate that is used in biomedical research due to its small size and relative ease of handling compared with larger primates. Although bone disease in common marmosets is well recognized, there are very few detailed descriptions in the literature that cover the range of lesions seen in these animals. For all animals used to model human disease, it is important to be aware of background lesions that may affect the interpretation of study findings. This retrospective study details bone diseases encountered in marmoset breeding colonies at 2 different institutions. Affected marmosets at Johns Hopkins University had lesions compatible with diagnoses of rickets, fibrous osteodystrophy and osteopenia. Affected marmosets at the Wisconsin National Primate Research Center exhibited severe lesions of osteoclastic bone resorption and remodeling that had an unusual distribution and were not easily categorized into a known disease entity. The purpose of this report is to document these naturally occurring skeletal lesions of common marmosets and suggest an approach to evaluating skeletal disease in prospective studies of these animals that will allow the most accurate diagnoses.

Concave distal end of ulna metaphysis alone is not a sign of rickets.

BACKGROUND: Statements have been made in the literature and in legal testimony that misrepresent the radiographic finding of concave distal end of the ulnar metaphysis. OBJECTIVE: To demonstrate that a concave distal end of the ossified ulna in infancy can be normal. MATERIALS AND METHODS: Eighty distal wrists of randomly selected infants in the first year of life with radiographic evidence that ruled out rickets were reviewed. RESULTS: In 16 of the cases (20%), mild or moderate concavity of the distal end of the ulna was seen. An intact metaphyseal collar of distal radius or ulna confirmed the absence of radiographic rickets. CONCLUSION: The finding of 20% of concave distal ulnas in the first year of life confirms the widely acknowledged statements that concave distal end of the ulna alone is not indicative of rickets. Statements to the contrary are not justified.

Rickets or abuse? A histologic comparison of rickets and child abuse-related fractures.

PURPOSE: The bone changes of vitamin D deficiency rickets have been invoked as an alternate explanation for child-abuse related fractures identified through medical imaging. The lack of modern histopathologic comparisons between these two entities limits the abilities of the forensic pathologist to address this differential diagnosis, both in their autopsy reports and on the witness stand. METHODS: We report a comparison of the histologic appearance of the bones in a two year old child with vitamin D deficiency rickets with fractures occurring in three young children with child abuse. RESULTS: In the case of rickets, there was marked architectural disorganization of endochondral ossification at the costochondral junctions and growth plates of long bones. The child abuse-related fractures showed osteochondral callus at different stages of healing, either centered on a discrete fracture line or at metaphyses (e.g. classical metaphyseal lesions). In many instances, the healing fractures disrupted the line of endochondral ossification. In none of the child abuse-related fractures was there any similarity to the histologic appearance of rickets. CONCLUSION: The maturation disturbance in the growth plate that occurs in rickets is a distinctive entity that cannot be confused histologically with healing fractures, including the classical metaphyseal lesion.

Rickets: Part II.

This is the continuation of a two-part review of rickets. This part emphasizes the specific pathophysiology, clinical features, pathoanatomy and radiographic findings of vitamin D deficiency rickets. Other forms of rickets, differential diagnostic considerations and the potential relationship between low levels of vitamin D metabolites and unexplained fractures in infants are also discussed.

Infantile osteopetrosis with superimposed rickets.

BACKGROUND: Rickets is a complication of infantile osteopetrosis and pre-treatment recognition of this complication is important. OBJECTIVE: To describe four children with infantile osteopetrosis complicated by rickets (osteopetrorickets) and review the relevant literature. MATERIALS AND METHODS: Retrospective chart analysis of four infants with osteopetrorickets and a systematic review of the relevant literature. RESULTS: We saw five children with infantile osteopetrosis, of whom four had superimposed rickets, for a period of 12 years. The review of the literature (including the current four children), yielded 20 children with infantile osteopetrorickets. The children ranged in age from 2 months to 12 months. In all children, hepatosplenomegaly was found. Sixteen (80%) children had visual impairments and eight (40%) children had hearing impairments. Serum calcium-phosphorus product was less than 30 in 18 children (90%). Twelve children (60%) were hypocalcemic and 18 (90%) were hypophosphatemic. In all children, the radiological examination demonstrated diffuse bony sclerosis and metaphyseal splaying and fraying of long bones. Five children (25%) had pathological fracture of extremities and 15 (75%) had rachitic rosary. CONCLUSION: Rickets as a complication to infantile osteopetrosis is not uncommon. Skeletal roentgenograms are of critical importance in the diagnosis of both osteopetrosis and superimposed rickets.

Rachitic changes, demineralization, and fracture risk in healthy infants and toddlers with vitamin D deficiency.

PURPOSE: To examine radiographic findings in children with vitamin D deficiency in comparison with biochemical marker levels and prevalence of fractures. MATERIALS AND METHODS: The parents or guardians of all participants provided written informed consent at the time of enrollment. The institutional review board approved the protocol, and HIPAA guidelines were followed. From a prospective sample of children seen for routine clinical care, 40 children with vitamin D deficiency (25-hydroxyvitamin D [25-OHD] level, ≤ 20 ng/mL) were identified, and high-detail computed radiographs of the wrists and knees were obtained. The children ranged in age from 8 to 24 months. Radiographs were scored by three readers with use of the 10-point Thacher score for rachitic changes and a five-point scale for demineralization. Serum calcium, phosphorus, alkaline phosphatase, and parathyroid hormone levels were determined. Fracture history was obtained for 35 of the 40 patients (88%). RESULTS: All readers identified rachitic changes at both readings in two patients (5%) and demineralization in two patients (5%). Interrater agreement was 65% for rachitic changes (κ = 0.33) and 70% for demineralization (κ = 0.37). When the majority of the raters determined that rachitic changes were absent at both readings, alkaline phosphatase levels were lower than those with other assessments (median, 267 vs 515 U/L [4.4589 vs 8.6005 µkat/L]; P = .01). When most raters determined that demineralization was present at both readings, serum 25-OHD levels were lower than those at other assessments (median, 9.0 vs 17.5 ng/mL [22.464 vs 43.68 nmol/L]; P = .02). No fractures were reported or identified radiographically. CONCLUSION: In infants and toddlers with vitamin D deficiency, rachitic changes and definite demineralization are uncommon and fracture risk is low.